A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.
A phase I dose-escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC-223 in patients with advanced solid tumors or multiple myeloma.
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DOI：
10.1002/cncr.29422
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发表时间：
2015-10-01
期刊：
影响因子：
6.2
通讯作者：
Munster PN
中科院分区：
文献类型：
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作者：
Bendell JC;Kelley RK;Shih KC;Grabowsky JA;Bergsland E;Jones S;Martin T;Infante JR;Mischel PS;Matsutani T;Xu S;Wong L;Liu Y;Wu X;Mortensen DS;Chopra R;Hege K;Munster PN
哺乳动物雷帕霉素靶蛋白（mTOR）通路对肿瘤的发展至关重要，但mTOR抑制剂已经产生了适度的结果。这项I期研究调查了mTORC 1/mTORC 2抑制剂CC-223在晚期癌症患者中的作用。晚期实体瘤或多发性骨髓瘤患者接受初始剂量为7.5 - 60 mg的CC-223，然后以28天为一个周期每天口服给药，直至疾病进展。主要目的是确定安全性、耐受性、非耐受剂量、最大耐受剂量（MTD）和初步药代动力学特征。次要目的是评价药效学效应并描述初步疗效。28例患者入组并接受了≥1剂CC-223。最常见的治疗相关3级不良事件为高血糖、疲乏和皮疹。4例患者出现剂量限制性毒性，包括高血糖症、皮疹、疲劳和粘膜炎。因此，确定45 mg/d为MTD。在接受CC-223 ≥45 mg/d的患者中，CC-223的药代动力学显示平均终末半衰期范围为4.86 - 5.64小时，观察到的最大血药浓度范围为269 - 480 ng/mL。CC-223 ≥30 mg/d可抑制血细胞中mTORC 1/mTORC 2通路生物标志物的磷酸化，并具有暴露-反应关系。最佳缓解包括1例部分缓解（乳腺癌;缓解持续时间220天; 30-mg/d队列）、疾病稳定（≥15 mg/d队列中8例患者;缓解持续时间范围36 - 168天）和疾病进展（12例患者）。疾病控制率为32%。CC-223是可耐受的，具有可管理的毒性。观察到初步抗肿瘤活性，包括肿瘤消退和mTORC 1/mTORC 2通路抑制的证据。Cancer 2015;121：3435-43.© 2015美国癌症协会。CC-223抑制mTORC 1和mTORC 2，这是一种被认为可以提高mTOR通路抑制效率的功能，将这种药物与雷帕霉素及其主要针对mTORC 1的类似物区分开来。在晚期实体瘤或多发性骨髓瘤患者的I期研究中，CC-223可耐受，毒性可管理，治疗与疾病控制的早期体征相关，包括肿瘤消退。
The mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC‐223 in patients with advanced cancer. Patients with advanced solid tumors or multiple myeloma received an initial dose of 7.5‐60 mg of CC‐223, followed by oral daily dosing in 28‐day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy. Twenty‐eight patients were enrolled and received ≥1 dose of CC‐223. The most common treatment‐related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose‐limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC‐223 demonstrated a mean terminal half‐life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC‐223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC‐223 ≥30 mg/d with an exposure‐response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30‐mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36‐168 days), and progressive disease (12 patients). The disease control rate was 32%. CC‐223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed. Cancer 2015;121:3435–43. © 2015 American Cancer Society. CC‐223 inhibits both mTORC1 and mTORC2, a feature thought to increase the efficiency of mTOR pathway suppression that distinguishes this agent from rapamycin and its analogs that primarily target mTORC1 alone. In a phase 1 study of patients with advanced solid tumors or multiple myeloma, CC‐223 was tolerable with manageable toxicities, and treatment was associated with early signs of disease control, including tumor regression.